Electrical Stimulation of Blood Vessels

ABSTRACT

Apparatus ( 20 ) is provided, including a bifurcation stent ( 50 ) comprising one or more electrodes ( 32 ), the stent ( 50 ) configured to be placed in a primary passage ( 52 ) and a secondary passage ( 54 ) of a blood vessel ( 30 ), and a control unit ( 34 ), configured to drive the electrodes ( 32 ) to apply a signal to a wall ( 36 ) of the blood vessel ( 30 ), and to configure the signal to increase nitric oxide (NO) secretion by the wall ( 36 ). Other embodiments are also described.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application claims the benefit of: (a) U.S. ProvisionalApplication 60/702,491, filed Jul. 25, 2005, entitled, “Electricalstimulation of blood vessels,” and (b) U.S. Provisional Application60/721,728, filed Sep. 28, 2005, entitled, “Electrical stimulation ofblood vessels,” both of which applications are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates generally to implantable medical devices,and specifically to methods and apparatus for stimulating and replacingblood vessels.

BACKGROUND OF THE INVENTION

U.S. Pat. Nos. 6,865,416 and 6,347,247 to Dev et al., which areincorporated herein by reference, describe methods for inducing orincreasing the vasodilation of a vessel, or the flow of bloodtherethrough, including applying an electrical impulse to the vessel.According to the inventors in the '416 and 247 applications, theinduction or increase of vessel vasodilation by an electrical impulseappears to result either from a direct effect caused by the electricalcurrent applied to the vessel, or an indirect effect resulting from therelease or stimulation of factors that promote vasodilation, such as therelease of endothelium derived relaxation factors (EDRF) currentlyidentified as nitric oxide (NO) or other vasodilating substancestriggered by the electrical pulses applied to the cells of the vessel.In an embodiment, a double-balloon catheter system incorporatingelectroporation technology is used to apply the electrical impulseendoluminally.

US Patent Application Publication 2003/0204206 to Padua et al., which isincorporated herein by reference, describes techniques for regulatingdelivery of therapeutic proteins and nucleic acids. The techniquesinclude using a genetically-engineered electrically-responsive promoteroperably linked to a therapeutic gene sequence, wherein expression ofsaid sequence is controlled by an electrical pulse generator. In anembodiment, the pulse generator is able to deliver charge balancedelectrical pulses at rate of about 10 to 100 Hz, preferably about 30 to80 Hz, and more preferably about 50 to 60 Hz. In an embodiment, animplantable system uses an RF signal to communicate and generate anelectrical current in a coiled stent. In an embodiment, an electricfield is applied to engineered cells grown on a scaffolding, usingeither a conductive matrix having parallel electrodes, or a conductivestent matrix.

U.S. Pat. No. 6,845,267 to Harrison et al., which is incorporated hereinby reference, describes an implantable control unit adapted to applystimulating drugs and/or electrical pulses to predetermined areasaffecting circulatory perfusion. In an embodiment, the implantablecontrol unit applies electrical stimulation directly to smooth muscle tomodulate its contractile state. The '267 patent states that relativelylow frequency electrical stimulation ([sic] than about 50-100 Hz) tendsto excite smooth muscle and lead to contraction, and relatively highfrequency electrical stimulation tends to relax smooth muscle and leadto dilation. In an embodiment, electrical and/or drug stimulation isapplied to autonomic sites responsible for innervation of the coronaryarteries, and/or directly to the smooth muscle surrounding thesearteries, in order to dilate the coronary arteries and provide relieffrom cardiac ischemia. For some applications, the implantable controlunit includes an electrical coil or other means of receiving energyand/or information inside the package, which receives power and/or databy inductive or radio-frequency (RF) coupling to a transmitting coilplaced outside the body. For some applications, the control unitcommunicates with other implanted stimulators, other implanted devices,and/or devices external to a patient's body, e.g., via an RF link, anultrasonic link, or an optical link.

U.S. Pat. No. 6,871,092 to Piccone, which is incorporated herein byreference, describes apparatus for the treatment of vascular, muscleand/or tendon disorders, for increasing the production of VascularEndothelial Growth Factor (VEGF), for anti-inflammatory treatment,and/or for the activation of microcirculation. The apparatus generatesand applies electrical pulses through the epidermis of a subject. Thepulses are described as inducing a biochemical response which not onlyeliminates inflammation from the part of the body treated and reduces oreliminates pain, but also has a rapid muscle-relaxant effect, andstimulates vasodilatation and VEGF production.

US Patent Application Publication 2004/0106954 to Whitehurst et al.,which is incorporated herein by reference, describes techniques fortreating congestive heart failure (CHF) by implanting of a dischargeportion of a catheter and, optionally, an electrode on a lead, neartissue to be stimulated. Stimulation pulses, such as drug infusionpulses and optional electrical pulses, are supplied by a stimulatorimplanted remotely, and through the catheter or lead, which is tunneledsubcutaneously between the stimulator and stimulation site. Stimulationsites include the coronary arteries, the aorta, the left ventricle, theleft atrium, and/or the pulmonary veins, among other locations. For someapplications, a stimulator includes electrical circuitry (including, forexample, an inductive coil) for receiving data and/or power from outsidethe body by inductive, radio frequency (RF), or other electromagneticcoupling. For some applications, the stimulator communicates with otherimplanted stimulators, other implanted devices, and/or devices externalto a patient's body via, e.g., an RF link, an ultrasonic link, a thermallink, and/or an optical link.

US Patent Application Publication 2006/0074453 to Kieval et al., whichis incorporated herein by reference, describes a method for treatingheart failure in a patient, including activating a baroreflex system ofthe patient with at least one baroreflex activation device andresynchronizing the patient's heart with a cardiac resynchronizationdevice. Activating the baroreflex system and resynchronizing the heartmay be performed simultaneously or sequentially, in various embodiments.A device for treating heart failure includes a baroreflex activationmember coupled with a cardiac resynchronization member. The baroreflexactivation member may comprise a wide variety of devices which utilizemechanical, electrical, thermal, chemical, biological, or other means toactivate baroreceptors and/or other tissues. In many embodiments,particularly the mechanical activation embodiments, the baroreflexdevice indirectly activates one or more baroreceptors by stretching orotherwise deforming the vascular wall surrounding the baroreceptors.

US Patent Application Publication 2003/0060858 to Kieval et al., whichis incorporated herein by reference, describes techniques forselectively and controllably reducing blood pressure, nervous systemactivity, and neurohormonal activity by activating baroreceptors. Abaroreceptor activation device is positioned near a baroreceptor, forexample a baroreceptor in the carotid sinus. A control system may beused to modulate the baroreceptor activation device. In someembodiments, the baroreceptor activation device takes the form of anintravascular deformable structure. The deformable structure deviceincludes a coil, braid or other stent-like structure disposed in thevascular lumen. In other embodiments, the baroreceptor activation devicetakes the form of an extravascular deformable structure, which isdisposed about the vascular wall, and therefore compresses, rather thanexpands, the vascular wall. The deformable structure device includes acoil, braid or other stent-like structure.

U.S. Pat. No. 6,086,527 to Talpade, which is incorporated herein byreference, describes a system for regulating blood flow to a portion ofthe vasculature, such as the renal system, in order to treat heartdisease. A regulator maintains blood flow so as to control physiologicalfeedback responses in order to relieve overload conditions on the heart.

US Patent Application Publication 2002/0103454 to Sackner et al., whichis incorporated herein by reference, describes methods of medicaltreatment and diagnosis using mediators released by endothelial cellsstimulated by external addition of pulses to the circulation. Theexternal pulses produce circumferential shear stress in body fluidchannels that subsequently stimulates the endothelial cells to producemediators that become available for therapeutic and diagnostic purposes.The preferred means of adding external pulses is the mechanicalinducement of periodic acceleration of the body or parts of the body bya reciprocating motion platform.

US Patent Application Publication 2005/0149130 to Libbus et al., whichis incorporated herein by reference, describes a baroreflex stimulatorincluding a pulse generator for providing a baroreflex stimulationsignal through an electrode, and a modulator to modulate the baroreflexstimulation signal based on a circadian rhythm template. In someembodiments, the stimulator includes a sensor to sense automatic nervoussystem (ANS) activity. Such a sensor can be used to perform feedback ina closed loop control system. For example, various embodiments sensesurrogate parameters, such as respiration and blood pressure, indicativeof ANS activity.

The following patents and patent application publications, all of whichare incorporated herein by reference, may be of interest:

U.S. Pat. No. 6,824,561 and US Patent Application Publication2004/0039417 to Soykan et al.

U.S. Pat. No. 6,810,286 to Donovan et al.

U.S. Pat. No. 6,463,323 to Conrad-Vlasak et al.

U.S. Pat. No. 6,058,331 to King

U.S. Pat. No. 6,200,259 to March

US Patent Application Publication 2003/0036773 to Whitehurst et al.

European Patent Application Publication EP 0 109 935 A1 to Charmillot etal.

Levenberg S et al., in an articled entitled, “Endothelial cells derivedfrom human embryonic stem cells,” Proc Natl Acad Sci USA 99(7):4391-6(2002) Epub 2002 Mar. 26, which is incorporated herein by reference,describe the differentiation steps of human embryonic stem cells intoendothelial cells forming vascular-like structures.

SUMMARY OF THE INVENTION

In some embodiments of the present invention, an electrode device isadapted to be inserted into a blood vessel. The electrode devicecomprises one or more electrodes that are adapted to apply an electricalsignal to a wall of the blood vessel, and to configure the signal toinduce an increase in nitric oxide (NO) secretion by the wall.

For some applications, stimulation using the electrode device causeshealing of the blood vessel. For example, the stimulation may (a) reducea level of atherosclerosis of the blood vessel, (b) have ananti-inflammatory and/or antithrombotic effect on the blood vessel, (c)increase endothelial cell growth, (d) reduce smooth muscle cell growth(e.g., to reduce blockage of the blood vessel), and/or (e) reduce plaqueactivity. For applications in which the blood vessel includes a coronaryartery, stimulation using the electrode device typically dilates thecoronary artery, thereby treating cardiac ischemia.

In some embodiments of the present invention, the electrode device isadapted to apply the signal to an artificial blood vessel graft that hasbeen implanted in the subject. Endothelial cells often grow into thelumen of such grafts. This growth is generally viewed as desirable.However, such growth sometimes causes platelets to accumulate in andthereby block the lumen. The signal applied by the electrode device isconfigured to induce an increase in NO secretion by the endothelialcells in the lumen, which increased NO secretion de-aggregates theplatelets. Alternatively or additionally, the signal applied by theelectrode device is configured to stimulate cell growth in the lumen ofthe artificial graft.

For some applications, the electrode device comprises at least onestent. The electrodes are coupled to the stent, or are integrated intostructural elements of the stent. For some applications, the stentcomprises a bifurcation stent. The electrode device is configured toinduce an increase in NO secretion by a wall of the blood vessel,typically in order to reduce platelet aggregation outside the stent(such as between the stent and the wall) and/or to minimize restenosis.

In some embodiments of the present invention, the electrode device isused to apply electrical stimulation during the process of derivingblood vessels (i.e., veins or arteries) from stem cells, such as fromembryonic stem cells. Alternatively or additionally, the electrodedevice is used to apply electrical stimulation to blood vessels derivedfrom stem cells after the blood vessels have been implanted in asubject. Further alternatively or additionally, the electrode device isused to apply electrical stimulation to tissue-based blood vesselscreated by another technique. An increase in NO production caused bysuch stimulation may be beneficial for the blood vessels, e.g., may aidthe process of differentiating the stem cells into the blood vessels.

In some embodiments of the present invention, a counterpulsation deviceis adapted to be inserted in an ascending aorta and/or a descendingaorta of a subject. The counterpulsation device comprises one or moreelectrodes, and an implantable or external control unit. The controlunit is adapted to drive the electrodes to apply an electrical signal toa wall of the aorta during systole, and to configure the signal toinduce an increase in NO secretion by the wall. The increased NOsecretion dilates the wall such that during systole the wall storesenergy, and pressure on the heart is reduced. During diastole, the wallconstricts, releasing the stored energy and thereby increasing bloodpressure and coronary blood flow. For some applications, the controlunit is additionally configured to drive the electrodes to apply, duringdiastole, stimulation configured to enhance the rapid constriction ofthe aorta.

In some embodiments of the present invention, an artificial artery isprovided that is configured to assume a first cross-sectional shapeduring a first phase of a cardiac cycle (e.g., systole or diastole), anda second cross-sectional shape during a second phase of the cardiaccycle (e.g., diastole or systole). Typically, both of thecross-sectional shapes are elliptical, and have major axes withdifferent lengths. For some applications, one of the cross-sectionalshapes is substantially circular (i.e., the major and minor axes aresubstantially the same). Such shape changing during each cardiac cyclegenerally reduces the likelihood of the artificial artery becomingblocked over time.

In an embodiment of the present invention, one or more electrodes areplaced in or adjacent to an eye of a subject, and are driven to apply asignal that induces NO production adjacent to the electrodes, in orderto treat an eye disease. For example, the increased NO production may beused to reduce intraocular pressure, in order to treat glaucoma.Alternatively or additionally, increased blood flow induced by arterialdilation cause by the NO production minimizes optic nerve degeneration,such as is seen in age-related macular degeneration (AMD). Alternativelyor additionally, the increased blood flow in one or more retinalarteries treats or prevents diabetic retinopathy.

There is therefore provided, in accordance with an embodiment of thepresent invention, apparatus including:

a bifurcation stent including one or more electrodes, the stentconfigured to be placed in a primary passage and a secondary passage ofa blood vessel; and

a control unit, configured to drive the electrodes to apply a signal toa wall of the blood vessel, and to configure the signal to increasenitric oxide (NO) secretion by the wall.

For some applications, the control unit is adapted to configure thesignal to reduce platelet aggregation outside the stent between thestent and the wall of the blood vessel.

For some applications, the control unit is configured to drive theelectrodes to apply the signal with a frequency of between 3 and 20 Hz,and/or a voltage of less than 5 volts.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for applying counterpulsation to an aortaof a subject, the apparatus including:

one or more electrodes, adapted to be inserted into the aorta; and

a control unit, configured to:

drive the electrodes to apply a systolic electrical signal to a wall ofthe aorta during at least a portion of systole,

configure the systolic signal to induce an increase in nitric oxide (NO)secretion by the wall, and

withhold driving the electrodes to apply the systolic signal to the wallduring at least a portion of diastole.

In an embodiment, the apparatus includes a physiological sensor, whichis configured to generate a sensor signal, and the control unit isconfigured to set at least one parameter of the systolic signalresponsively to the sensor signal.

For some applications, the control unit is configured to drive theelectrodes to begin application of the systolic signal slightly prior toa commencement of systole. For some applications, the control unit isconfigured to drive the electrodes to begin application of the systolicsignal less than 50 ms prior to a commencement of systole.

For some applications, the control unit is adapted to configure thesystolic signal to have an amplitude of between 1 and 10 mA, and/or afrequency of less than 30 Hz.

In an embodiment, the control unit is adapted to drive the electrodes toapply a diastolic electrical signal to the wall during at least aportion of diastole, and to configure the diastolic signal to enhanceconstriction of the aorta during diastole. For some applications, thecontrol unit is adapted to configure a diastolic value of a parameter ofthe diastolic signal to be between 1.5 and 4 times a systolic value ofthe parameter of the systolic signal, the parameter selected from thegroup consisting of: an amplitude, and a frequency. For someapplications, the control unit is adapted to configure the diastolicsignal to have an amplitude of between 5 and 20 mA, and/or a frequencyof between 15 and 100 Hz.

In an embodiment, the apparatus includes an element configured tomechanically dilate the aorta during at least a portion of systole. Forsome applications, the element is configured to be placed at leastpartially in the aorta. Alternatively or additionally, the element isconfigured to be placed at least partially outside the aorta. For someapplications, the element is configured to serve as at least one of theone or more electrodes.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus including an artificial artery configuredto assume a first cross-sectional shape during a first phase of acardiac cycle, and a second cross-sectional shape during a second phaseof the cardiac cycle.

For some applications, exactly one of the first and secondcross-sectional shapes is substantially circular.

For some applications, the first and second phases include systole anddiastole, respectively, and the artificial artery is configured toassume the first and second cross-sectional shapes during systole anddiastole, respectively.

In an embodiment, the first and second cross-sectional shapes areelliptical, having respective major axes having first and secondlengths, respectively. For some applications, a ratio of the firstlength to the second length is at least 1.1, such as at least 1.3.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus for treating an eye of a subject, theapparatus including:

one or more electrodes, configured to be placed at least partially inthe eye; and

a control unit, configured to treat the eye by driving the electrodes toapply an electrical signal to the eye that induces production of nitricoxide (NO).

In an embodiment, the control unit is configured to drive the electrodesto apply the signal to induce the NO production sufficiently to inducedilation of a retinal artery of the subject.

In an embodiment, the control unit is configured to drive the electrodesto apply the signal to induce the NO production sufficiently to minimizedegeneration of an optic nerve of the subject.

For some applications, the control unit is configured to be placed inthe eye, and the apparatus includes a photovoltaic cell that isconfigured to power the control unit. For some applications, at leastone of the electrodes includes a coil that is configured to receiveenergy inductively from the control unit. For some applications, atleast one of the electrodes is configured to be placed at a siteposterior to a retina of the eye.

In an embodiment, the control unit is configured to drive the electrodesto apply the signal to induce the NO production sufficiently to reducean intraocular pressure of the eye. For some applications, theelectrodes are configured to be placed around a cornea of the eye, andthe control unit is configured to drive the electrodes to apply thesignal to induce the NO production in a vicinity of a trabecularmeshwork of the eye.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus for application to a blood vessel ofa subject, the apparatus including:

one or more electrodes, configured to be placed in or outside the bloodvessel in a vicinity of a baroreceptor of the subject, such that theelectrodes are in electrical communication with the blood vessel; and

a control unit, configured to drive the electrodes to apply anelectrical signal to the blood vessel, and to configure the signal toinduce an increase in nitric oxide (NO) secretion by a wall of the bloodvessel sufficiently to cause dilation of the wall, thereby activatingthe baroreceptor.

In an embodiment, the apparatus includes an element configured tomechanically dilate the blood vessel in the vicinity of thebaroreceptor. In an embodiment, the electrodes are configured to applymechanical force to the wall that is sufficient to change a shape of thewall.

In an embodiment, the apparatus includes a sensor configured to sense afeature of a cardiac cycle of the subject and to output a sensor signalresponsively thereto, and the control unit is configured to drive theelectrodes to apply the signal responsively to the sensor signal. Forsome applications, the control unit is configured to apply the signalduring at least a portion of systole, and to withhold applying thesignal during at least a portion of diastole.

In an embodiment, the electrodes are configured to be placed in theblood vessel, and are shaped so as to define springy rib-shapedelements. For some applications, the apparatus includes one or morepiezoelectric elements positioned in direct or indirect mechanicalcontact with the rib-shaped elements, and the apparatus is configuredsuch that pulsing of the blood vessel causes the piezoelectric elementsto generate power, and the control unit is configured to use the powerto drive the electrodes to apply the signal.

There is also provided, in accordance with an embodiment of the presentinvention, a method including:

placing a bifurcation stent including one or more electrodes in aprimary passage and a secondary passage of a blood vessel;

driving the electrodes to apply a signal to a wall of the blood vessel;and

configuring the signal to increase nitric oxide (NO) secretion by thewall.

There is further provided, in accordance with an embodiment of thepresent invention, a method for applying counterpulsation to an aorta ofa subject, the method including:

applying a systolic electrical signal to a wall of the aorta during atleast a portion of systole;

configuring the systolic signal to induce an increase in nitric oxide(NO) secretion by the wall; and

withholding applying the systolic signal to the wall during at least aportion of diastole.

There is still further provided, in accordance with an embodiment of thepresent invention, a method including:

providing an artificial artery configured to assume a firstcross-sectional shape during a first phase of a cardiac cycle, and asecond cross-sectional shape during a second phase of the cardiac cycle;and

grafting the artificial artery to a natural artery of the subject.

In an embodiment, grafting includes grafting during a coronary bypassprocedure.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for treating a subject, including:

identifying that the subject suffers from a condition of an eye; and

treating the eye condition by inducing production of nitric oxide (NO)in the eye by applying an electrical signal to the eye.

In an embodiment, identifying includes identifying that the subjectsuffers from glaucoma, and applying the signal includes configuring thesignal to induce the NO production sufficiently to reduce an intraocularpressure of the eye. For some applications, applying the signal includesapplying the signal around a cornea of the eye to induce the NOproduction in a vicinity of a trabecular meshwork of the eye.

There is also provided, in accordance with an embodiment of the presentinvention, a method including:

applying an electrical signal to a blood vessel of a subject in avicinity of a baroreceptor of the subject; and

activating the baroreceptor by configuring the signal to induce anincrease in nitric oxide (NO) secretion by a wall of the blood vesselsufficiently to cause dilation of the wall.

There is further provided, in accordance with an embodiment of thepresent invention, a method including:

implanting an artificial blood vessel in a subject;

applying an electrical signal to the artificial blood vessel; and

configuring the signal to induce an increase in nitric oxide (NO)secretion by endothelial cells that grow in a lumen of the artificialblood vessel.

In an embodiment, configuring the signal includes configuring the signalto induce the NO secretion to de-aggregate platelets accumulated as aresult of growth of the endothelial cells. In an embodiment, configuringthe signal includes configuring the signal to induce growth of theendothelial cells in the lumen. In an embodiment, configuring the signalincludes configuring the signal to have a frequency of between 3 and 20Hz.

For some applications, configuring the signal includes configuring thesignal to have a voltage of less than 5 volts.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for deriving a blood vessel from stem cells,including:

inducing the stem cells to differentiate into the blood vessel;

applying an electrical signal to at least one cell selected from thegroup consisting of: one of the stem cells, a cell of the blood vesselas the blood vessel is being derived, and a cell of the blood vesselafter the blood vessel has been derived; and

configuring the signal to induce an increase in nitric oxide (NO)secretion by the selected at least one cell.

In an embodiment, the at least one cell includes at the one of the stemcells, and applying the signal includes applying the signal to the oneof the stem cells. In an embodiment, the at least one cell includes thecell of the blood vessel as the blood vessel is being derived, andapplying the signal includes applying the signal to the cell of theblood vessel as the blood vessel is being derived. In an embodiment, theat least one cell includes the cell of the blood vessel after the bloodvessel has been derived, and applying the signal includes applying thesignal to the cell of the blood vessel after the blood vessel has beenderived.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method including:

identifying buildup of plaque on a wall of a blood vessel of a subjectas being in a vicinity of a baroreceptor of the subject; and

increasing flexibility of the artery in the vicinity by removing theplaque from the artery.

In an embodiment, the blood vessel is selected from the group consistingof: a carotid artery, and an aorta in a vicinity of an aortic arch.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of an electrode device adapted to beinserted into a blood vessel of a subject, in accordance with anembodiment of the present invention;

FIG. 2 is a schematic illustration of the electrode device of FIG. 1comprising a bifurcation stent, in accordance with an embodiment of thepresent invention;

FIG. 3 is a schematic illustration of another configuration of theelectrode device of FIG. 1, in accordance with an embodiment of thepresent invention;

FIG. 4 is a schematic illustration of yet another configuration of theelectrode device of FIG. 1, in accordance with an embodiment of thepresent invention;

FIG. 5 is a schematic illustration of a counterpulsation device insertedin an ascending aorta of a subject, in accordance with an embodiment ofthe present invention; and

FIG. 6 is a schematic cross-sectional illustration of an artificialartery, in accordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS

FIG. 1 is a schematic illustration of an electrode device 20 adapted tobe inserted into a blood vessel 30 of a subject, in accordance with anembodiment of the present invention. Electrode device 20 comprises oneor more electrodes 32, and an implantable or external control unit 34.Control unit 34 is adapted to drive electrodes 32 to apply an electricalsignal to a wall 36 of blood vessel 30, and to configure the signal toinduce an increase in nitric oxide (NO) secretion by wall 36. For someapplications, wall 36 secretes the NO into the lumen of blood vessel 30.Alternatively or additionally, wall 36 secretes the NO into tissue ofthe blood vessel. For some applications, blood vessel 30 includes anatherosclerotic blood vessel. For some applications, blood vessel 30includes a coronary artery, a bypass graft (such as a coronary arterybypass graft (CABG)), a retinal artery, a pancreatic artery, or a penileartery (e.g., to treat erectile dysfunction). The applied signal treatserectile dysfunction by functioning as a pump to enhance blood flow(e.g., for a diabetic patient), and/or by generating NO as a signalingmolecule which enhances erection.

For some applications, stimulation using electrode device 20 causeshealing of blood vessel 30. For example, the stimulation may (a) reducea level of atherosclerosis of the blood vessel, (b) have ananti-inflammatory and/or antithrombotic effect on the blood vessel, (c)increase endothelial cell growth, (d) reduce smooth muscle cell growth(e.g., to reduce blockage of blood vessel 30), and/or (e) reduce plaqueactivity. For some applications, electrode device 20 is configured todrive electrodes 32 to apply the signal for a period of at least oneweek, such as at least one month, or at least several months. Suchlong-term stimulation may contribute to healing of the blood vessel. Forapplications in which blood vessel 30 includes a coronary artery,stimulation using electrode device 20 typically dilates the coronaryartery, thereby treating cardiac ischemia.

In an embodiment of the present invention, electrode device 20 isadapted to apply the signal to an artificial blood vessel graft that hasbeen implanted in the subject. Endothelial cells often grow into thelumen of such grafts. This growth is generally viewed as desirable.However, such growth sometimes causes platelets to accumulate in andthereby block the lumen. The signal applied by electrode device 20 isconfigured to induce an increase in NO secretion by the endothelialcells in the lumen, which increased NO secretion de-aggregates theplatelets. Alternatively or additionally, the signal applied byelectrode device 20 is configured to stimulate cell growth in the lumenof the artificial graft. These stimulation techniques may be used, forexample, with synthetic vascular grafts manufactured by W. L. Gore &Associates (Newark, Del., USA).

In an embodiment of the present invention, electrode device 20 comprisesat least one stent 40. For some applications, electrodes 32 are coupledto stent 40, as shown in FIG. 1. Alternatively or additionally,structural elements of stent 40 additionally serve as one or more ofelectrodes 32. For some applications, electrodes 32 comprise ringelectrodes, as shown in FIG. 1. For some applications, electrodes 32comprise elongated cylinders, through which blood can flow(configuration not shown). In an embodiment, electrodes 32 are nothollow, and blood does not pass through them. Instead, for example, theelectrodes may effectively be point electrodes, or be shaped as needleelectrodes that slightly penetrate tissue adjacent thereto. It is thusto be seen that various shapes may be appropriate for electrodes 32,depending on each particular application.

Reference is made to FIG. 2, in which stent 40 is shown comprising abifurcation stent 50, in accordance with an embodiment of the presentinvention. Control unit 34 is adapted to induce an increase in NOsecretion by wall 36 of blood vessel 30, typically in order to reduceplatelet aggregation outside the stent, such as between the stent andwall 36. For some applications, electrode device 20 comprises two ormore stents 40, at least a first one of which is adapted to be placed ina primary passage 52 of blood vessel 30, and at least a second one ofwhich is adapted to be placed in a secondary passage 54 of blood vessel30 in a vicinity of a bifurcation 56.

The particular lattice configuration of stent 40 shown in FIGS. 1 and 2is for illustrative purposes only. Stent 40 may comprise otherconfigurations known in the art. For some applications, stent 40comprises two elements arranged in a double helix (configuration notshown). Typically, one of the elements serves as an anode and the otheras a cathode of electrodes 32.

FIG. 3 is a schematic illustration of another configuration of electrodedevice 20, in accordance with an embodiment of the present invention. Inthis embodiment, electrodes 32 are springy, and are configured to expandinto contact with wall 36 of blood vessel 30. For example, theelectrodes may be shaped so as define springy rib-shaped elements. Forsome applications, electrodes 32 are configured to apply a sufficientmechanical force to wall 36 to change a shape of the wall. For someapplications, electrode device 20 is configured to be placed in avicinity of a baroreceptor, and to both apply an electrical signal tothe baroreceptor and change the shape of wall 36 in the vicinity of thebaroreceptor. For some applications, the springiness of ribs of theelectrodes is adjustable, such as by mechanical, electrical, or thermalmeans (e.g., at least a portion of the electrodes may comprisesnitinol). The springiness may be mechanically adjusted by sliding aportion of the ribs into a chamber such that such portion is no longerspringy.

For some applications, electrode device 20 comprises one or morepiezoelectric elements positioned in direct or indirect mechanicalcontact with the ribs of the electrodes. Pulsing of blood vessel 30causes the piezoelectric elements to generate sufficient power forapplying the electrical signal.

FIG. 4 is a schematic illustration of yet another configuration ofelectrode device 20, in accordance with an embodiment of the presentinvention. In this embodiment, electrodes 32 are configured to expandinto contact with wall 36 of blood vessel 30. Electrodes 32 are insertedinto blood vessel 30 using a catheter 60. The electrodes are stored inthe catheter in a contracted position. After the catheter has beenadvanced to a desired location in the blood vessel, the catheter iswithdrawn from the blood vessel, exposing the electrodes and allowingthem to expand against the wall of the blood vessel. For someapplications, catheter 60 is additionally used to remove electrodes 32from blood vessel 30 after treatment. The catheter is advanced over theelectrodes, causing the electrodes to contract and be stored in thecatheter. The catheter, holding the electrodes, is then withdrawn fromthe blood vessel. Alternatively, the electrodes are withdrawn withoutusing the catheter, because their orientation within the blood vesselallows them to be freed from their contact points with the blood vesselby pulling the lead connecting the electrodes.

In an embodiment of the present invention, control unit 34 is adapted todrive only a portion of electrodes 32 at any given time. For someapplications, control unit 34 drives only a portion of the electrodes bysending a multiplexed signal to all of the electrodes over a set ofwires. For example, control unit 34 may use time-division,frequency-division, or digital multiplexing. To enable suchmultiplexing, each electrode typically comprises a microchip thatinterprets whether the signal generated by control unit 20 is intendedto cause the electrode to apply a current to tissue in its vicinity. Theuse of these multiplexing techniques typically allows the use of only afew (e.g., 3-4) wires to control all of the electrodes.

Reference is now made to FIGS. 1-4. For some applications, control unit34 is adapted to configure the signal applied by electrodes 32 to haveone or both of the following parameters: a frequency of between about 3and about 20 Hz (e.g., between about 5 and about 10 Hz), and/or avoltage less than about 5 V. For some applications, the signal ismonophasic, while for other applications the signal is biphasic. Forsome applications, the control unit applies the signal having a dutycycle (e.g., about 1-15%, or about 15-50%).

In an embodiment of the present invention, all or a portion of electrodedevice 20 is biodegradable, and is adapted to degrade after remaining inblood vessel 30 for a certain period of time. For some applications,only the portions of electrode device 20 that are placed in blood vessel30 are biodegradable, while control unit 34 is not biodegradable. In anembodiment, the portions of electrode device 20 in blood vessel 30comprise a biodegradable carbon polymer or a biodegradable sugarpolymer. As appropriate, one or both of these polymers has metalparticles dispersed therein in order to provide suitable electrodeproperties.

Reference is again made to FIG. 1. For some applications, control unit34 is coupled to electrode device 20 over wires 38. Control unit 34 isimplanted in the body of the subject outside blood vessel 30, or ispositioned external to the body of the subject. For other applicationscontrol unit 34 is wirelessly coupled to electrode device 20, forwireless transmission of energy and/or data. For example, the controlunit may be inductively coupled to the electrode device, or the controlunit may comprise an ultrasonic transducer that transmits energy to theelectrode device, which receives the energy using an ultrasonictransducer, such as a piezoelectric transducer. For some applications,stent 40 itself serves as an antenna for receiving inductive energyand/or a wireless data signal from control unit 34. Control unit 34comprises a power source, such as a battery, or a galvanic power source(in which case, separate ones of electrodes 32 may function as the anodeand cathode of a galvanic cell).

In an embodiment of the present invention, electrode device 20 isconfigured to release a local or systemic drug into blood vessel 30,such as an anticoagulation agent (e.g., heparin), an immunosuppressiveagent (e.g., sirolimus), a chemotherapy agent (e.g., taxol), a hormone(e.g., estradiol), or an NO-releasing compound.

In an embodiment of the present invention, electrode device 20 isadapted to be placed in direct contact with cardiac muscle of thesubject, so as to induce an increase in NO secretion by the cardiacmuscle.

In an embodiment of the present invention, electrode device 20 isadapted to be placed in contact with non-vascular smooth muscle (e.g.,smooth muscle of the gastrointestinal tract).

In an embodiment of the present invention, electrode device 20 isadapted to be placed in an eye of a subject, and to induce dilation of aretinal artery, for example to treat diabetic retinopathy. For someapplications, electrode device 20 comprises a small coil, which receivesenergy inductively in order to drive current into the tissue in contacttherewith or adjacent thereto. The energy may be released by inductivelydriving current flow in the tissue, or via an electrode coupled to thecoil. As appropriate based on surgical constraints or the particularpathology to be treated, the coil may be placed in an anterior orposterior position within the globe of the eye, or, alternatively,posterior to the retina.

In an embodiment of the present invention, one or more electrodes areplaced in or adjacent to the subject's eye, and are driven to apply asignal that induces NO production adjacent to the electrodes, in orderto treat an eye disease. For example, the increased NO production may beused to reduce intraocular pressure, in order to treat glaucoma.Alternatively or additionally, increased blood flow induced by the NOproduction minimizes optic nerve degeneration, such as is seen inage-related macular degeneration (AMD). Alternatively or additionally,as noted hereinabove, the increased blood flow in one or more retinalarteries treats or prevents diabetic retinopathy.

In an embodiment of the present invention, a system for treatingglaucoma comprises one or more electrodes (e.g., exactly two electrodes)which are adapted to placed around a cornea of the eye, and a controlunit which drives the electrodes to apply a signal that induces NOproduction in a vicinity of the trabecular meshwork of the eye. Such NOproduction enhances the flow of aqueous humour through the trabecularmeshwork to Schlemm's canal, thereby reducing intraocular pressure totreat glaucoma.

For some applications, the control unit is configured (including beingsufficiently small) to be placed in the eye, and the system comprises aphotovoltaic cell that is configured to power the control unit.

In an embodiment of the present invention, electrode device 20 is usedto apply electrical stimulation during the process of deriving bloodvessels (i.e., veins or arteries) from stem cells, such as fromembryonic stem cells. Alternatively or additionally, electrode device 20is used to apply electrical stimulation to blood vessels derived fromstem cells after the blood vessels have been implanted in a subject. Anincrease in NO production caused by such stimulation may be beneficialfor the blood vessels, e.g., may aid the process of differentiating thestem cells into the blood vessels. These stimulation techniques may beused, for example, in conjunction with techniques for differentiatingstem cells into blood vessels described in the above-mentioned articleby Levenberg S et al.

Reference is made to FIG. 5, which is a schematic illustration of acounterpulsation device 70 inserted in an ascending aorta 72 of asubject, in accordance with an embodiment of the present invention. FIG.5 shows insertion into ascending aorta 72 by way of illustration and notlimitation, and the scope of the present invention includes,alternatively or additionally, inserting device 70 into the descendingaorta. Additionally, it is noted that the size of device 70 may beconsiderably longer than as shown in FIG. 5 (e.g., 5-15 cm, or 15-30cm), depending on the extent of the counterpulsation effect that isdesired.

Counterpulsation device 70 comprises one or more electrodes 74, and animplantable or external control unit 76. Control unit 76 is adapted todrive electrodes 74 to apply an electrical signal to a wall of ascendingaorta 72 during systole, and to configure the signal to induce anincrease in NO secretion by the wall. The increased NO secretion dilatesthe wall such that during systole the wall stores energy, and pressureon the heart is reduced. During diastole, the wall constricts, releasingthe stored energy and thereby increasing blood pressure and coronaryblood flow. For some applications, control unit 76 is additionallyconfigured to drive electrodes 74 to apply, during diastole, stimulationconfigured to enhance the rapid constriction of aorta 72.

In an embodiment, electrodes 74 are driven to apply a signal duringsystole that is about 1-10 mA (e.g., about 1-7 mA, or about 4-10 mA,typically about 4-5 mA) at about 1-30 Hz (e.g., about 1-20 Hz, or about10-30 Hz, typically about 10 Hz). For some applications, the signalapplied during diastole has an amplitude and/or a signal frequency thatis between about 1.5 and 4 times the corresponding value during systole.In an embodiment, electrodes 74 are driven to apply a signal duringdiastole that is about 5-20 mA (e.g., about 10 mA) at a frequency thatis between about 15 and 100 Hz, e.g., about 50 Hz.

For some applications, counterpulsation device 70 is about 25 cm long,and induces a 10% dilation of aorta 72 and, in turn, an approximately 40cc increase in volume along 25 cm of the aorta. For some applications,counterpulsation device 70 is used to treat a subject suffering fromcongestive heart failure (CHF), while for other applications, the deviceis used to treat non-CHF subjects, such as subjects suffering from highsystolic blood pressure.

For some applications, counterpulsation device 70 comprises at least onephysiological sensor 78, such as an electrocardiogram (ECG) monitor, ora pressure sensor. Control unit 76 determines the one or more parametersof the signal application (such as a timing parameter) responsively to asensor signal generated by sensor 78. For some applications, controlunit 76 is adapted to drive electrodes 74 to apply the signal everyheart beat, while for other applications the signal is applied less thanevery heartbeat, such as once every several heartbeats. For someapplications, the control unit is configured to drive the electrodes tobegin application of the systolic signal slightly prior to the beginningof systole (e.g., less than 50 ms prior to the beginning of systole),which generally enhances the induced dilation of the aorta.

For some applications, counterpulsation device 70 alternatively oradditionally comprises an element configured to mechanically dilateascending aorta 72 (or the descending aorta) during at least a portionof systole, by causing the aorta to assume a more elliptical shape. Forsome applications, the element is placed within the aorta, while forother applications the element is placed outside the aorta. For example,the element may comprise one or more magnets and/or coils, which aredriven to change the shape of the element using electricity,piezoelectric elements, and/or hydraulic pressure. For someapplications, the element both applies the mechanical force andfunctions as one or more of electrodes 74. For applications in whichboth the electrical signal and mechanical force is applied duringsystole, the counterpulsation effect is intensified by the combinationof the electrically-induced dilation, the mechanically-induced change incross-sectional shape, and the natural expansion of the aorta duringsystole.

For some applications, counterpulsation device 70 is applied to anartery other than an aorta.

Reference is made to FIG. 6, which is a schematic cross-sectionalillustration of an artificial artery 100, in accordance with anembodiment of the present invention. Artificial artery 100 is typicallyused as a graft for a coronary bypass procedure. For some applications,artificial artery 100 has a diameter of less than 7 mm, such as lessthan 5 mm or less than 3 mm. Artificial artery 100 is configured toassume a first cross-sectional shape 102 during a first phase of acardiac cycle (e.g., systole or diastole), and a second cross-sectionalshape 104 during a second phase of the cardiac cycle (e.g., diastole orsystole). Typically, one or both of the cross-sectional shapes areelliptical, and have major axes with different lengths L1 and L2,respectively. For some applications, one of the cross-sectional shapesis substantially circular. For some applications, a ratio of L1 to L2 isgreater than 1.1, 1.2, 1.3, 1.4, or 1.5. Such shape changing during eachcardiac cycle generally reduces the likelihood of artificial artery 100becoming blocked over time. Without wishing to be bound by anyparticular theory, the inventor hypothesizes that the frequent shapechanges of arteries in skeletal muscle, caused by movement of themuscle, may help prevent blockage of these arteries. The shape changesof artificial artery 100 may have the same general beneficial effect.

In an embodiment of the present invention, an electrode device comprisesone or more electrodes. The electrode device is configured to be placedoutside of a blood vessel, such as an artery, in a vicinity of the bloodvessel, such that the electrodes remain outside the blood vessel inelectrical communication with the blood vessel. An implantable orexternal control unit is configured to drive the electrodes to apply anelectrical signal to the blood vessel, and to configure the signal toinduce an increase in nitric oxide (NO) secretion by a wall of the bloodvessel. For some applications, the electrode device comprises aplurality of electrodes, and the control unit is configured to randomlyor quasi-randomly activate a subset of the electrodes, and repeatedlychange which electrodes are in the subset. For some applications, theelectrode device is shaped as a tube having an inner surface to whichthe electrodes are coupled. For some applications, the electrode devicecomprises at least one elongated lead, which is configured to be placedin the blood vessel, and to serve as an electrode having a polarityopposite that of the electrodes outside the blood vessel.

In an embodiment of the present invention, a system comprises anelectrode device and an implantable or external control unit. Theelectrode device comprises one or more electrodes configured to beplaced in or outside a blood vessel in a vicinity of a baroreceptor. Thecontrol unit drives the electrodes to apply to the blood vessel anelectrical signal that induces NO secretion by a wall of the artery.Such NO secretion causes dilation of the wall of the blood vessel,thereby activating the baroreceptor. For some applications, the systemcomprises a sensor for sensing a feature of a cardiac cycle, and thecontrol unit is configured to synchronize the signal application withthe feature. For example, the control unit may be configured to applythe signal once per heart beat, or every nth heart beat, such as everysecond or third heart beat. For some applications, the control unitapplies the signal only during systole. For some applications, thesystem comprises a blood pressure sensor, and the control unit drivesthe electrode device to apply the signal responsively to a sensed bloodpressure. For example, the blood vessel may be the carotid artery or theaorta in a vicinity of the aortic arch.

Alternatively or additionally, the system comprises an elementconfigured to mechanically dilate the blood vessel in the vicinity ofthe baroreceptor, such as during systole, as described above. For someapplications, the element is placed within the blood vessel, while forother applications the element is placed outside the blood vessel. Forexample, the element may comprise one or more magnets and/or coils,which are driven to change the shape of the element using electricity,piezoelectric elements, and/or hydraulic pressure. For someapplications, the element is configured to store energy during one phaseof the cardiac cycle, and use the stored energy to change the shape ofthe element during another phase of the cardiac cycle. For someapplications, the element for applying the mechanical force also servesas one or more of the electrodes.

For some applications, the element is configured to cause thecross-sectional shape of the blood vessel to be more elliptical duringdiastole than the shape would otherwise be (it being noted that rigidblood vessels generally have a substantially circular cross-sectionalshape). As a result, the baroreceptor typically detects more shapechange during systole that it otherwise would. For example, the elementmay be configured to function as a weak spring in order to change thecross-sectional shape.

In an embodiment of the present invention, a treatment method comprisesremoving plaque from an artery in a vicinity of a baroreceptor, in orderto increase flexibility of the artery and thus sensitivity of thebaroreceptor. For example, the SilverHawk™ Plaque Excision System(FoxHollow Technologies, Inc., Redwood City, Calif.) may be used toremove the plaque.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

1. Apparatus comprising: a bifurcation stent comprising one or more electrodes, the stent configured to be placed in a primary passage and a secondary passage of a blood vessel; and a control unit, configured to drive the electrodes to apply a signal to a wall of the blood vessel, and to configure the signal to increase nitric oxide (NO) secretion by the wall. 2-4. (canceled)
 5. Apparatus for applying counterpulsation to an artery of a subject, the apparatus comprising: one or more electrodes, adapted to be inserted into the artery; and a control unit, configured to: drive the electrodes to apply a systolic electrical signal to a wall of the artery during at least a portion of systole, configure the systolic signal to induce an increase in nitric oxide (NO) secretion by the wall, and withhold driving the electrodes to apply the systolic signal to the wall during at least a portion of diastole.
 6. The apparatus according to claim 5, comprising a physiological sensor, which is configured to generate a sensor signal, wherein the control unit is configured to set at least one parameter of the systolic signal responsively to the sensor signal.
 7. The apparatus according to claim 5, wherein the control unit is configured to drive the electrodes to begin application of the systolic signal slightly prior to a commencement of systole.
 8. The apparatus according to claim 5, wherein the control unit is configured to drive the electrodes to begin application of the systolic signal less than 50 ms prior to a commencement of systole.
 9. The apparatus according to claim 5, wherein the control unit is adapted to configure the systolic signal to have an amplitude of between 1 and 10 mA.
 10. The apparatus according to claim 5, wherein the control unit is adapted to configure the systolic signal to have a frequency of less than 30 Hz.
 11. The apparatus according to claim 5, wherein the control unit is adapted to drive the electrodes to apply a diastolic electrical signal to the wall during at least a portion of diastole, and to configure the diastolic signal to enhance constriction of the artery during diastole.
 12. The apparatus according to claim 11, wherein the control unit is adapted to configure a diastolic value of a parameter of the diastolic signal to be between 1.5 and 4 times a systolic value of the parameter of the systolic signal, the parameter selected from the group consisting of: an amplitude, and a frequency.
 13. The apparatus according to claim 11, wherein the control unit is adapted to configure the diastolic signal to have an amplitude of between 5 and 20 mA.
 14. The apparatus according to claim 11, wherein the control unit is adapted to configure the diastolic signal to have a frequency of between 15 and 100 Hz.
 15. The apparatus according to claim 5, comprising an element configured to mechanically dilate the aorta during at least a portion of systole.
 16. The apparatus according to claim 15, wherein the element is configured to be placed at least partially in the aorta.
 17. The apparatus according to claim 15, wherein the element is configured to be placed at least partially outside the aorta.
 18. The apparatus according to claim 15, wherein the element is configured to serve as at least one of the one or more electrodes.
 19. Apparatus comprising an artificial artery configured to assume a first cross-sectional shape during a first phase of a cardiac cycle, and a second cross-sectional shape during a second phase of the cardiac cycle. 20-24. (canceled)
 25. Apparatus for treating an eye of a subject, the apparatus comprising: one or more electrodes, configured to be placed at least partially in the eye; and a control unit, configured to treat the eye by driving the electrodes to apply an electrical signal to the eye that induces production of nitric oxide (NO). 26-32. (canceled)
 33. Apparatus for application to a blood vessel of a subject, the apparatus comprising: one or more electrodes, configured to be placed in or outside the blood vessel in a vicinity of a baroreceptor of the subject, such that the electrodes are in electrical communication with the blood vessel; and a control unit, configured to drive the electrodes to apply an electrical signal to the blood vessel, and to configure the signal to induce an increase in nitric oxide (NO) secretion by a wall of the blood vessel sufficiently to cause dilation of the wall, thereby activating the baroreceptor.
 34. The apparatus according to claim 33, comprising an element configured to mechanically dilate the blood vessel in the vicinity of the baroreceptor.
 35. The apparatus according to claim 33, wherein the electrodes are configured to apply mechanical force to the wall that is sufficient to change a shape of the wall.
 36. The apparatus according to claim 33, comprising a sensor configured to sense a feature of a cardiac cycle of the subject and to output a sensor signal responsively thereto, and wherein the control unit is configured to drive the electrodes to apply the signal responsively to the sensor signal.
 37. The apparatus according to claim 36, wherein the control unit is configured to apply the signal during at least a portion of systole, and to withhold applying the signal during at least a portion of diastole.
 38. The apparatus according to claim 33, wherein the electrodes are configured to be placed in the blood vessel, and are shaped so as to define springy rib-shaped elements.
 39. The apparatus according to claim 38, comprising one or more piezoelectric elements positioned in direct or indirect mechanical contact with the rib-shaped elements, wherein the apparatus is configured such that pulsing of the blood vessel causes the piezoelectric elements to generate power, and wherein the control unit is configured to use the power to drive the electrodes to apply the signal.
 40. A method comprising: placing a bifurcation stent including one or more electrodes in a primary passage and a secondary passage of a blood vessel; driving the electrodes to apply a signal to a wall of the blood vessel; and configuring the signal to increase nitric oxide (NO) secretion by the wall. 41-43. (canceled)
 44. A method for applying counterpulsation to an artery of a subject, the method comprising: applying a systolic electrical signal to a wall of the artery during at least a portion of systole; configuring the systolic signal to induce an increase in nitric oxide (NO) secretion by the wall; and withholding applying the systolic signal to the wall during at least a portion of diastole.
 45. The method according to claim 44, wherein applying the systolic signal comprises sensing a physiological parameter of the subject, and setting at least one parameter of the systolic signal responsively to the sensed physiological parameter.
 46. The method according to claim 44, wherein applying the systolic signal comprises beginning applying the systolic signal less than 50 ms prior to a commencement of systole.
 47. The method according to claim 44, wherein applying the systolic signal comprises configuring the systolic signal to have an amplitude of between 1 and 10 mA.
 48. The method according to claim 44, applying the systolic signal comprises configuring the systolic signal to have a frequency of less than 30 Hz.
 49. The method according to claim 44, comprising applying a diastolic electrical signal to the wall during at least a portion of diastole, and configuring the diastolic signal to enhance constriction of the artery during diastole.
 50. The method according to claim 49, wherein applying the diastolic signal comprises configuring a diastolic value of a parameter of the diastolic signal to be between 1.5 and 4 times a systolic value of the parameter of the systolic signal, the parameter selected from the group consisting of: an amplitude, and a frequency.
 51. The method according to claim 49, wherein applying the diastolic signal comprises configuring the diastolic signal to have an amplitude of between 5 and 20 mA.
 52. The method according to claim 49, applying the diastolic signal comprises configuring the diastolic signal to have a frequency of between 15 and 100 Hz.
 53. The method according to claim 44, comprising mechanically dilating the aorta during at least a portion of systole.
 54. The method according to claim 53, wherein mechanically dilating comprises mechanically dilating the aorta from within the aorta.
 55. The method according to claim 53, wherein mechanically dilating comprises mechanically dilating the aorta from outside the aorta.
 56. A method comprising: providing an artificial artery configured to assume a first cross-sectional shape during a first phase of a cardiac cycle, and a second cross-sectional shape during a second phase of the cardiac cycle; and grafting the artificial artery to a natural artery of the subject. 57-62. (canceled)
 63. A method for treating a subject, comprising: identifying that the subject suffers from a condition of an eye; and treating the eye condition by inducing production of nitric oxide (NO) in the eye by applying an electrical signal to the eye. 64-70. (canceled)
 71. A method comprising: applying an electrical signal to a blood vessel of a subject in a vicinity of a baroreceptor of the subject; and activating the baroreceptor by configuring the signal to induce an increase in nitric oxide (NO) secretion by a wall of the blood vessel sufficiently to cause dilation of the wall.
 72. The method according to claim 71, comprising mechanically dilating the blood vessel in the vicinity of the baroreceptor.
 73. The method according to claim 71, wherein applying the signal comprises sensing a feature of a cardiac cycle of the subject, and applying the signal responsively to the sensed feature.
 74. The method according to claim 73, wherein applying the signal comprises applying the signal during at least a portion of systole, and withholding applying the signal during at least a portion of diastole.
 75. A method comprising: implanting an artificial blood vessel in a subject; applying an electrical signal to the artificial blood vessel; and configuring the signal to induce an increase in nitric oxide (NO) secretion by endothelial cells that grow in a lumen of the artificial blood vessel. 76-79. (canceled)
 80. A method for deriving a blood vessel from stem cells, comprising: inducing the stem cells to differentiate into the blood vessel; applying an electrical signal to at least one cell selected from the group consisting of: one of the stem cells, a cell of the blood vessel as the blood vessel is being derived, and a cell of the blood vessel after the blood vessel has been derived; and configuring the signal to induce an increase in nitric oxide (NO) secretion by the selected at least one cell. 81-83. (canceled)
 84. A method comprising: identifying buildup of plaque on a wall of a blood vessel of a subject as being in a vicinity of a baroreceptor of the subject; and increasing flexibility of the artery in the vicinity by removing the plaque from the artery.
 85. (canceled)
 86. The apparatus according to claim 5, wherein the artery includes a coronary artery of the subject and wherein the one or more electrodes are configured to be inserted into the coronary artery.
 87. The apparatus according to claim 5, wherein the artery includes an aorta of the subject and wherein the one or more electrodes are configured to be inserted into the aorta.
 88. The apparatus according to claim 5, wherein, at least one time, the control unit is configured to drive only a portion of the electrodes.
 89. The apparatus according to claim 88, wherein the control unit is configured to activate the electrodes in a sequence by time dividing the activation of the electrodes.
 90. The apparatus according to claim 33, wherein the blood vessel includes a carotid artery of the subject, and wherein the one or more electrodes are configured to be placed in or outside of the carotid artery in the vicinity of the baroreceptor.
 91. The apparatus according to claim 33, wherein the blood vessel includes an aorta of the subject, and wherein the one or more electrodes are configured to be placed in or outside of the aorta in the vicinity of the baroreceptor.
 92. The apparatus according to claim 33, further comprising a plaque removal device which is configured to increase flexibility of the blood vessel in the vicinity by removing plaque from the artery.
 93. The apparatus according to claim 33, further comprising a sensor configured to sense a blood pressure of the subject and to output a sensor signal responsively thereto, and wherein the control unit is configured to drive the electrodes to apply the signal responsively to the sensor signal.
 94. The apparatus according to claim 33, further comprising an element which is configured to facilitate an assumption of an elliptical shape by the blood vessel in the vicinity, during diastole of the subject.
 95. The apparatus according to claim 94, wherein the element comprises the one or more electrodes, and wherein the one or more electrodes are configured to facilitate the assumption of the elliptical shape by the blood vessel in the vicinity, during diastole of the subject.
 96. The apparatus according to claim 94, wherein the element is configured to be placed within the blood vessel.
 97. The apparatus according to claim 94, wherein the element is configured to be implanted outside of the blood vessel.
 98. The apparatus according to claim 94, wherein the element comprises a spring.
 99. The apparatus according to claim 94, wherein the element comprises at least one of the electrodes.
 100. The apparatus according to claim 34, wherein the element configured to dilate the blood vessel comprises a magnet.
 101. The apparatus according to claim 34, wherein the element configured to dilate the blood vessel comprises a coil.
 102. The apparatus according to claim 34, wherein the element configured to dilate the blood vessel comprises a piezoelectric element.
 103. The apparatus according to claim 34, wherein the element is configured to dilate the blood vessel using electricity.
 104. The apparatus according to claim 34, wherein the element is configured to dilate the blood vessel using hydraulic pressure.
 105. The apparatus according to claim 36, wherein the control unit is configured to drive the electrodes to apply the signal during intermittent heartbeats.
 106. The method according to claim 71, wherein the blood vessel includes a carotid artery of the subject and applying the electrical signal to the blood vessel comprises applying the electrical signal to the carotid artery.
 107. The method according to claim 71, wherein the blood vessel includes an aorta of the subject and applying the electrical signal to the blood vessel comprises applying the electrical signal to the aorta.
 108. The method according to claim 71, further comprising increasing flexibility of the blood vessel in the vicinity of the baroreceptor by removing plaque from the blood vessel in the vicinity.
 109. The method according to claim 71, wherein applying the signal comprises sensing a blood pressure of the subject and applying the signal responsively to the sensed blood pressure.
 110. The method according to claim 71, further comprising coupling an element to the blood vessel, wherein the coupling of the element to the blood vessel facilitates an assumption of an elliptical shape by the blood vessel in the vicinity, during diastole of the subject.
 111. The method according to claim 110, wherein coupling the element to the blood vessel comprises placing the element within the blood vessel.
 112. The method according to claim 110, wherein coupling the element to the blood vessel comprises implanting the element outside of the blood vessel.
 113. The method according to claim 110, wherein the element includes a spring and coupling the element to the blood vessel comprises coupling the spring to the blood vessel.
 114. The method according to claim 110, wherein the element includes an electrode, and wherein coupling the element to the blood vessel comprises coupling the electrode to the blood vessel.
 115. The method according to claim 72, wherein dilating the blood vessel comprises dilating the blood vessel with a magnet.
 116. The method according to claim 72, wherein dilating the blood vessel comprises dilating the blood vessel with a coil.
 117. The method according to claim 72, wherein dilating the blood vessel comprises dilating the blood vessel with a piezoelectric element.
 118. The method according to claim 72, wherein dilating the blood vessel comprises dilating the blood vessel using electricity.
 119. The method according to claim 72, wherein dilating the blood vessel 30 comprises dilating the blood vessel using hydraulic pressure.
 120. The method according to claim 73, wherein applying the signal comprises applying the signal during intermittent heartbeats.
 121. A method for activating a baroreceptor of a subject, comprising: coupling an element having an elliptical cross-section to a blood vessel of the subject in a vicinity of the baroreceptor, by implanting the element; and activating the baroreceptor by facilitating, with the elliptical-shaped element, an assumption of an elliptical shape by the blood vessel in a vicinity of the baroreceptor, during diastole of the subject.
 122. The method according to claim 121, wherein the blood vessel includes a carotid artery of the subject and coupling the element comprises coupling the element to the carotid artery.
 123. The method according to claim 121, wherein the blood vessel includes an aorta of the subject and coupling the element comprises coupling the element to the aorta.
 124. The method according to claim 121, wherein implanting the element comprises placing the element within the blood vessel.
 125. The method according to claim 121, wherein implanting the element comprises implanting the element outside of the blood vessel.
 126. The method according to claim 121, wherein the element includes a spring and implanting the element comprises coupling the spring to the blood vessel.
 127. Apparatus for activating a baroreceptor of a subject, comprising: an implantable elliptical shaped element which is configured to facilitate an assumption of an elliptical shape by a blood vessel in a vicinity of the baroreceptor of the subject, during diastole of the subject.
 128. The apparatus according to claim 127, wherein the blood vessel includes a carotid artery of the subject, and wherein the element is configured to facilitate an assumption of an elliptical shape by the carotid artery in the vicinity of the baroreceptor, during diastole.
 129. The apparatus according to claim 127, wherein the blood vessel includes an aorta of the subject, and wherein the element is configured to facilitate an assumption of an elliptical shape by the aorta in the vicinity of the baroreceptor, during diastole.
 130. The apparatus according to claim 127, wherein the element is configured to be placed within the blood vessel.
 131. The apparatus according to claim 127, wherein the element is configured to be implanted outside of the blood vessel.
 132. The apparatus according to claim 127, wherein the element comprises a spring.
 133. The method according to claim 44, wherein the artery includes a coronary artery of the subject and wherein applying the systolic electrical signal to the wall of the artery comprises applying the systolic electrical signal to a wall of the coronary artery.
 134. The method according to claim 44, wherein the artery includes an aorta of the subject and wherein applying the systolic electrical signal to the wall of the artery comprises applying the systolic electrical signal to a wall of the aorta.
 135. The method according to claim 44, wherein applying the systolic electrical signal comprises applying the systolic electrical signal through a plurality of electrodes, and, at least one time, applying the systolic electrical signal via a first portion of the electrodes and not via a second portion of the electrodes.
 136. The method according to claim 135, wherein applying the systolic electrical signal comprises activating a set electrodes in a sequence by time dividing the activation of the electrodes.
 137. The apparatus according to claim 5, wherein the control unit is configured drive the electrodes to apply a biphasic systolic signal
 138. The apparatus according to claim 11, wherein the control unit is configured to drive the electrodes to apply a biphasic diastolic signal.
 139. The apparatus according to claim 5, further comprising an element configured to mechanically dilate the aorta.
 140. The apparatus according to claim 139, wherein the element is configured to be placed at least partially in the aorta.
 141. The apparatus according to claim 139, wherein the element is configured to be placed at least partially outside the aorta.
 142. The apparatus according to claim 139, wherein the element is configured to serve as at least one of the one or more electrodes.
 143. The apparatus according to claim 139, wherein the element configured to dilate the blood vessel comprises a magnet.
 144. The apparatus according to claim 139, wherein the element configured to dilate the blood vessel comprises a coil.
 145. The apparatus according to claim 139, wherein the element configured to dilate the blood vessel comprises a piezoelectric element.
 146. The apparatus according to claim 139, wherein the element is configured to dilate the blood vessel using electricity.
 147. The apparatus according to claim 139, wherein the element is configured to dilate the blood vessel using hydraulic pressure.
 148. Apparatus comprising: one or more electrodes configured to be placed on a wall of a blood vessel; and a control unit, configured to reduce platelet aggregation in a vicinity of the blood vessel wall by driving the electrodes to apply a signal to the blood vessel wall and by configuring the signal to increase nitric oxide (NO) secretion by the wall.
 149. Apparatus comprising: one or more electrodes configured to be placed in a vicinity of a blood vessel bifurcation; and a control unit, configured to drive the electrodes to apply a signal to a wall of the blood vessel in the vicinity, and to configure the signal to increase nitric oxide (NO) secretion by the wall.
 150. The apparatus according to claim 149, wherein the control unit is configured to reduce platelet aggregation in the vicinity of the bifurcation by increasing the NO secretion.
 151. The method according to claim 44, wherein applying the systolic electrical signal comprises applying a biphasic systolic signal.
 152. The method according to claim 49, wherein applying the diastolic electrical signal comprises applying a biphasic diastolic signal.
 153. The method according to claim 44, further comprising mechanically dilating the aorta.
 154. The method according to claim 153, wherein mechanically dilating the aorta comprises mechanically dilating the aorta from within the aorta.
 155. The method according to claim 153, wherein mechanically dilating the aorta comprises mechanically dilating the aorta from outside the aorta.
 156. The method according to claim 153, wherein mechanically dilating the aorta comprises mechanically dilating the aorta using an electrode.
 157. The method according to claim 153, wherein dilating the blood vessel comprises dilating the blood vessel with a magnet.
 158. The method according to claim 153, wherein dilating the blood vessel comprises dilating the blood vessel with a coil.
 159. The method according to claim 153, wherein dilating the blood vessel comprises dilating the blood vessel with a piezoelectric element.
 160. The method according to claim 153, wherein dilating the blood vessel comprises dilating the blood vessel using electricity.
 161. The method according to claim 153, wherein dilating the blood vessel comprises dilating the blood vessel using hydraulic pressure.
 162. A method comprising: placing one or more electrodes inside a blood vessel; driving the electrodes to apply a signal to a wall of the blood vessel; and reducing platelet aggregation inside the blood vessel by configuring the signal to increase nitric oxide (NO) secretion by the wall.
 163. A method comprising: placing one or more electrodes in a primary passage and a secondary passage of a blood vessel; driving the electrodes to apply a signal to a wall of the blood vessel; and reducing platelet aggregation inside the blood vessel by configuring the signal to increase nitric oxide (no) secretion by the wall. 